Laminin-411 is a vascular ligand for MCAM and facilitates TH17 cell entry into the CNS

PLoS One. 2012;7(7):e40443. doi: 10.1371/journal.pone.0040443. Epub 2012 Jul 6.


TH17 cells enter tissues to facilitate pathogenic autoimmune responses, including multiple sclerosis (MS). However, the adhesion molecules involved in the unique migratory capacity of TH17 cells, into both inflamed and uninflamed tissues remain unclear. Herein, we characterize MCAM (CD146) as an adhesion molecule that defines human TH17 cells in the circulation; following in vitro restimulation of human memory T cells, nearly all of the capacity to secrete IL-17 is contained within the population of cells expressing MCAM. Furthermore, we identify the MCAM ligand as laminin 411, an isoform of laminin expressed within the vascular endothelial basement membranes under inflammatory as well as homeotstatic conditions. Purified MCAM-Fc binds to laminin 411 with an affinity of 27 nM, and recognizes vascular basement membranes in mouse and human tissue. MCAM-Fc binding was undetectable in tissue from mice with targeted deletion of laminin 411, indicating that laminin 411 is a major tissue ligand for MCAM. An anti-MCAM monoclonal antibody, selected for inhibition of laminin binding, as well as soluble MCAM-Fc, inhibited T cell adhesion to laminin 411 in vitro. When administered in vivo, the antibody reduced TH17 cell infiltration into the CNS and ameliorated disease in an animal model of MS. Our data suggest that MCAM and laminin 411 interact to facilitate TH17 cell entry into tissues and promote inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD146 Antigen / metabolism
  • CHO Cells
  • Cell Movement
  • Cell Polarity
  • Cell Proliferation
  • Choroid Plexus / immunology
  • Choroid Plexus / metabolism*
  • Choroid Plexus / pathology
  • Cricetinae
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Extracellular Matrix / metabolism
  • Female
  • Humans
  • Interleukin-17 / metabolism
  • Interleukin-1beta / physiology
  • Interleukins / metabolism
  • Laminin / physiology*
  • Ligands
  • Mice
  • Mice, Knockout
  • Protein Binding
  • Th17 Cells / metabolism
  • Th17 Cells / physiology*


  • CD146 Antigen
  • Interleukin-17
  • Interleukin-1beta
  • Interleukins
  • LAMA4 protein, human
  • LAMB1 protein, human
  • Laminin
  • Ligands
  • MCAM protein, human
  • laminin gamma 1
  • interleukin-22